All vertebrates have an immune system. A vertebrate with a severely defective immune system will soon die unless extraordinary measures are taken to isolate it from a variety of infectious agents (e.g., bacteria, viruses, fungi and parasites). A properly functioning immune system is able to distinguish "nonself" cells from "self" cells and, therefore, selectively destroys and eliminates nonself cells such as invading organisms, while leaving self cells intact.
However, some nonself cells evade the host's immune system by camouflaging their outer surface with host protein. These camouflaged nonself cells remain and proliferate in the host undetected. Undetected nonself cells are the cause of many diseases, which plague man and animals. For example, cells infected with viral diseases (e.g., AIDS, influenza, measles, mumps, chicken pox, shingles, hepatitis, diabetes) bacterial diseases (e.g., pneumonia, bronchitis, meningitis. cardititis, periodontitis, bovine mastitis) and fungal diseases (e.g., histoplasmosis, blastomycosis, candidiasis), all result from the infection and proliferation of nonself cells in a host vertebrate.
In addition, cancer results when a vertebrate's own cells become nonself. Healthy individuals at any given moment carry about 50,000-100,000 nonself, potentially malignant cells in their body. These nonself cells are generally recognized and killed by the individual's immune system. However, if any of the nonself cells become camouflaged, they will proliferate as cancer.
Currently, there are not adequate and specific therapies for most diseases that result from the presence of nonself cells in a host. For example, cancer is currently treated either by surgical excision of tumors or by therapies using radiation and highly toxic chemicals. However, surgical excission is not an effective method of treatment where the cancer has metastasized. In addition, radiation and chemotherapy are nonspecific. Therefore, normal cells are often killed in addition to cancerous cells.
Another problem is that the cell-kill caused by chemotherapeutic agents follow first-order kinetics. As a result, a constant percentage, rather than a constant number of cells is killed by a given application of a chemotherapeutic agent. To illustrate, if a drug capable of killing 99.99 % of malignant cells is administered to a patient, who harbors 10.sup.12 malignant cells, 10.sup.8 malignant cells would remain. Although the patient would be diagnosed as having a complete clinical remission, any of the 10.sup.8 malignant cells remaining could cause a relapse in the disease.
Still another problem with cancer therapies and therapies for other diseases based on the presence of nonself cells in a host is that the nonself cells constantly become resistant to a particular therapeutic agent over time. Attempts to overcome this problem have resulted in protocols whereby several therapeutic agents are used concurrently or in rational sequences. Other protocols are aimed at targeting the drugs more specifically to the nonself cells.
A chemotherapeutic agent that could be used to specifically eliminate nonself cells, but not self cells in vivo would be very useful in treating cancer and a variety of other diseases that result from the presence of nonself cells in a host.
Alpha-ketoaldehydes, a series of chemicals containing the alpha-ketoaldehyde radical, are known as potent inhibitors of the proliferation of nonself cells. The antiviral properties of alpha ketoaldehydes have been intensively and systematically examined and the results published in a series of papers (Underwood, G.E. and S.D. Weed, Proc. Soc. Exp. Biol. Med., 93:421-424 (1956); Tiffany, B.D. et al. J. Am. Chem. Soc., 79:1682 (1957); Underwood. G.E. et al., Proc. Soc. Exp. Biol. Med., 100:312 (1959)). Alpha-ketoaldehydes have also been shown to have a bacteriostatic effect. (Freedberg, W.B. et al. J. Bacteriol., 108:137 (1971); Barrett, P.A. et al. Nature, 206:1340 (1965); Egyud, L.G. and A. Szent-Gyorgy, Proc. Natl. Acad. Sci., USA, 55:388-393 (1966)). In addition, topical treatment of tumor growth with alpha-ketoaldehydes cures the host (Apple, M.A. and D.M. Greenberg, Can. Chem. Ther. Rep., 51:455-464 (1967); Egyud, L. and A. Szent-Gyorgy, Science, 160:1140 (1968); Jerzykowski, T. et al., Neoplasma, 17:25-35 (1970)).
However, alpha-ketoaldehydes exhibit a relatively high toxicity in animals. Moreover, they are readily metabolized to the corresponding .beta.-hydroxy acids by glyoxalase enzymes, which are present in all living cells, especially red blood cells. Therefore, although free alpha-ketoaldehydes inhibit the proliferation of nonself cells, systemic doses of alpha-ketoaldehydes have not been used therapeutically.